Historical records suggest that the human population of the world is overdue for a new pandemic of influenza. What can be done in preparation for this event? Most important is to gain an understanding of the molecular epidemiological events that will occur and are responsible for the origin of pandemic virus. This knowledge can then be utilized to mobilize preventive measures. Current strategies would use vaccine and antiviral technologies and would at best only blunt the impact of the pandemic in a few regions of the world. The long term objective of this proposal is to generate knowledge that may be used to prepare for and prevent the appearance of pandemic influenza viruses. During the present granting period we established that the Asian/57 and Hong Kong/68 human pandemic viruses emerged by reassortment between the Eurasian (Europe/Asia) lineage of avian influenza viruses and those in humans. The data further support the notion that pigs are the "reassortment vessel" and that the pandemic viruses originated in China. Our current findings indicate that avian influenza viruses have recently spread to pigs in Europe and reassortants containing human and avian influenza gene segments have been isolated from humans in The Netherlands. Of great potential significance is the recent detection of avian influenza virus in pigs from China. Our specific aims will determine: 1) Are pigs a risk factor in the genesis of human pandemic viruses? 2) Will the avian influenza viruses in pigs in China become the precursors of the next human pandemic? 3) Establish what molecular changes are associated with transmission of avian influenza viruses to mammalian hosts and utilize this information to develop epidemiological probes for their detection. The availability of nucleotide sequence information and molecular probes to the different lineages of influenza viruses provide a unique opportunity to elucidate the events that occur during emergence of a new pandemic influenza virus and may establish principles that apply to other emerging infectious diseases.